Technical Field
This invention is directed to an improved process for the preparation of compounds of Formula (I), which are useful as PDE10 inhibitors. In particular, the present invention is directed to an improved process for the preparation of 1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanone (Compound 1001), which is useful as a PDE10 inhibitor.
Description of the Related Art
Compounds of Formula (I) are known and potent inhibitors of PDE10:

wherein:                A is:        
                R1 is C1-6alkyl, C1-6haloalkyl, C1-6aralkyl, aryl, —(CH2)nO(CH2)mCH3 or —(CH2)nN(CH3)2;        R2 is (i) substituted or unsubstituted aryl or (ii) substituted or unsubstituted heterocyclyl;        R3 is substituted or unsubstituted aryl;        R4 is hydrogen, C1-6alkyl or C1-6haloalkyl;        n is 1, 2, 3, 4, 5 or 6; and        m is 0, 1, 2, 3, 4, 5 or 6.        
Compounds of Formula (II) are known and potent inhibitors of PDE10:

wherein:                Q is S or O; and        X is Cl or Br.        
The compounds having the structure of Formula (I), Formula (II), Formula (III) and Compound 1001 fall within the scope of PDE10 inhibitors disclosed in International PCT Application Publication No. WO 2011/112828. Compound 1001 (1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanone) is specifically disclosed as compound no. 65-10; Compound 1002 (1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone) is specifically disclosed as compound no. 47-1; and Compound 1003 (1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone) is specifically disclosed as compound no. 63-1 in International PCT Application No. WO 2011/112828. The compounds having the structure of Formula (I), Formula (II), and compounds 1001-1003 can be prepared according to the general procedures found in International PCT Application Publication No. WO 2011/112828, which are herein incorporated by reference.
The compounds of Formula (II) and Compound 1001 in particular have a complex structure and their synthesis is very challenging. Known synthetic methods face practical limitations and are not economical for large-scale production. There is a need for efficient manufacture of the compounds of Formula (II) and Compound 1001, in particular, with a minimum number of steps, good chemical purity, and sufficient overall yield. Known methods for production of the compounds of Formula (II) and Compound 1001, in particular, have limited yield. The present invention fulfills these needs and provides further related advantages.